The discovery of multiple receptors for opium alkaloids and their derivatives, or opiates, has attracted considerable interest among research investigators because the physiologic responses mediated by subpopulations of these receptors differ. See W. R. Martin, Pharmacol. Review, 35, 283 (1983). Thus, compounds that are highly selective for a single subpopulation of receptors may have clinical utility because undesired pharmacologic effects at other opioid receptor populations would be minimal.
Although selective antagonist compounds are available for mu and delta receptor types, the development of kappa-selective opioid antagonists has been elusive.
In J. Med. Chem., 25, 847 (1982) M. Erez, A. E. Takemori and P. S. Portoghese reported the synthesis of a bivalent compound containing two beta-naltrexamine pharmacophores connected by a oligoethylenoxy spanner. This compound, designated TENA, can be represented by the formula: ##STR2##
TENA was found to be about 27 times more effective in antagonizing the activity of the kappa receptor agonist, U50488H, relative to the mu receptor agonist, morphine, and it was about five times more effective against the kappa receptor agonist, ethylketazocine, relative to morphine. See P. S. Portoghese et al., Life Sciences, 36, 801 (1985).
However, due to the implication of the kappa opioid receptor in the mediation of important physiological responses such as appetite and traumatic paralysis, a need exists for compounds which can more selectively block kappa opioid receptor sites.